Adrenal insufficiency symptoms / Addison disease

Adrenal insufficiency symptoms

What is adrenal insufficiency?

Adrenal insufficiency (Addison disease) is a disease which can be divided into primary adrenal insufficiency and secondary adrenal insufficiency. Primary adrenal insufficiency is associated with adrenal gland or also known as adrenal failure. Secondary adrenal failure is associated with hypothalamus- pituitary axis.

Primary adrenal insufficiency is due to the lack of production of mineralocorticoids ( aldosterone) , glucocorticoids ( cortisol ) and sex androgen ( which is more common in primary adrenal insufficiency). The signs and symptoms are not specific and may mimic viral infection and anorexia nervosa. (Anorexia nervosa presents with low potassium level while adrenal insufficiency presents with high potassium level)

What are the causes of adrenal insufficiency?

Primary adrenal insufficiency (due to destruction of the adrenal cortex) is caused by:

-Autoimmunity ( >70% in the UK ) . It is associated with autoantibodies mediated adrenalitis which form part of autoimmune polyglandular syndrome.

Autoimmune polyglandular syndrome can be divided into:

Type 1 ( monogene syndrome ) - The present of the AIRE gene on chromosome 2 is detected. It may present with chronic mucatenous candidiasis, hypoparathyroidism and Addison disease (adrenal insufficiency).

Type 2 ( Schmidt syndrome ) - It may present with autoimmune thyroid disease, Addison disease ( adrenal insufficiency ), pericarditis, pleuritis and diabetes mellitus type 1.

Type 3 - Autoimmune thyroid disease and other autoimmune condition (except Addison disease).

Type 4 - Combination of all autoimmune conditions not included above.

- Tuberculosis ( TB infection ) and histoplasmosis.

- Opportunistic infection in HIV patient (Mycobacterium avium and CMV).

- Infiltration ( adrenal metastases ( breast, lung and renal carcinoma ) and melanoma,

- Amyloidosis

- Late onset of congenital adrenal hyperplasia


- Thrombophilia and lupus anticoagulant syndrome

- meningococcal septicemia ( adrenal hemorrhage - Waterhouse- Friederichsen syndrome)

- Surgery ( bilateral adrenalectocmy)

- Leukodystrophy (ACTH receptor mutation) that present with adrenal atrophy and demyelination .

- Drugs ( ketoconazole, rifampicin and etomidate) .

Secondary adrenal insufficiency is associated with deficiency of ACTH. ACTH deficiency is associated with chronic glucocorticoid therapy. This will reduce the endogenous glucocorticoid response ( e.g. In stress). This will finally lead to atrophy of corticotroph cell of the pituitary. This is more prominent with the withdrawal of long term steroid / glucocorticoid therapy. Other causes that lead to failure to increase the glucocorticoids may also lead to secondary adrenal failure such as gastrointestinal disturbance, infection or intercurrent illness. Mineralocorticoids level is maintained in secondary adrenal insufficiency as it is regulated by renin angiotensin region in the adrenal.

Both types of adrenal insufficiency develop progressively, however any vascular events such as infarction / hemorrhage may lead to sudden loss of pituitary and adrenal function.

How common is an adrenal insufficiency ( Addison disease ) ?

Adrenal insufficiency is rare. However it may result in fatality. The incidence of primary adrenal insufficiency (Addison disease) is 0.6 per 100 000 while the prevalence is 10 per 100 000.

Addison disease is common in the 4th decades. Women are twice than men to get Addison disease and autoimmune disease account more than 70% of cases of primary adrenal insufficiency.

The prevalence of secondary adrenal insufficiency is 28 per 100 000. Commonly affect female in six decades due to long term steroid therapy.

What are the risk factors for adrenal insufficiency?

Adrenal insufficiency is associated with other autoimmune disease such as pernicious anemia, Graves disease, Hashimoto thyroiditis, and HLA DR3 and HLA DR4 and vitiligo. Addison disease is also part of triple A syndrome that consists of alacrimation and achalasia.

How does the patient present?

History and examination

In acute adrenal insufficiency ( Addisonian crisis) , patients may present with nausea, vomiting, nonspecific abdominal pain, hypotension, tachycardia, increase in temperature, pyrexia, pale, cold and clammy as well as coma. In the case of pituitary apoplexy patient may complains of headache and visual disturbance.

In chronic adrenal insufficiency, such as primary adrenal insufficiency / Addison disease, patient may present with tanned, lean , tiredness, lethargy, weakness, tearful, suffer from abdominal pain , vomiting, nausea, constipation and depression as well as psychosis and low self esteem as a result of depletion of adrenal androgen, Patient may present with hyperpigmentation of Palmar crease, buccal mucosa, scars, nails and any pressure points as well as light exposed area as a result of ACTH cross reacts with melanocytes/ melanin. The patient may also develop rare cases of salt craving, myalgia and arthralgia. In females, decrease in androgen level may lead to decrease in libido and androgen dependent body hair. Male is not affected as androgen is synthesized in the testes.Postural hypotension may also develop. Hypoglycemic is also common in patients. The patient may also present with vitiligo.

Chronic secondary adrenal insufficiency may appear pale and present with signs and symptoms of pituitary / hypothalamus disease such as visual disturbance and headache as a result of mass effect.

What is the pathology behind adrenal insufficiency?

Primary adrenal insufficiency pathology depends on the underlying causes. In tuberculosis, the adrenal is enlarged with the present of epitheloid granuloma which later leads to caseation and finally calcification.

In autoimmunity causes, the adrenal is atrophy with lymphatic infiltration and adrenal medulla is preserved.

In Waterhouse- Friederich syndrome there is a bilateral adrenal hemorrhage that begins in the adrenal medulla.

In secondary adrenal insufficiency, the patient may present in adrenal atrophy and preservation of the zona glomerulosa.

How to investigate adrenal insufficiency?

The investigations require justifying the present of adrenal insufficiency may include:

Blood test - The blood test may include full blood count to indicate anemia and neutrophilia. Urea and electrolytes test is performed and it will indicate a decrease in sodium level and increase in potassium level. This condition shows reduction in mineralocorticoid synthesis / aldosterone synthesis. Calcium levels may increase while glucose level will decrease as a result of the decrease in glucocorticoid synthesis.

Blood culture, ESR and CRP (increase in acute infection) as well as urea (increase in dehydration) may also perform.

Serum cortisol and serum ACTH level measurement - Serum cortisol level > 550 nmol/l is normal while serum cortisol level < 150 nmol/l indicates adrenal insufficiency.

Synacthen test is a test to measure the serum cortisol level. It is divided into short and long synacthen test.

The short synacthen test requires 250 microgram of tetracosatride ( synacthen ) injected intramuscularly to the individual. Then the serum cortisol is measured at 0 min, 30 min and 60 min to measure the adrenal reserve of the cortisol. Normal response may produce serum cortisol > 550 nmol/l. serum cortisol level < 150 nmol/l indicates adrenal insufficiency.

The Long synacthen test is performed to detect the presence of secondary adrenal insufficiency. 1000microgram tetracosatride (synacthen) is injected intramuscularly and the basal cortisol level is measured at 0 min, 30 min, 60 min, 90min, 120min, then 2hr, 4hr, 6hr, 8hr, 10hr and 12 yr. The cortisol level will rise in secondary adrenal insufficiency due to atrophy of the adrenal gland responds to ACTH while not in primary adrenal insufficiency as the gland has been maximally stimulated by endogenous ACTH.

Urine culture and analysis is important to detect any infection. Plasma 21- hydroxylase -adrenal antibody test is important to detect any autoimmune disease associated with Addison disease. Plasma renin activity is useful to identify the deficiency of the mineralocorticoid in adrenal insufficiency.

Thyroid function test (TFT) is useful to detect the presence of hypothyroidism ( increase in TSH and the decrease in T4 and T3 ). This is followed by re evaluation of TFT as glucocorticoid treatment and replacement may raise the thyroid stimulating hormone ( TSH ).

Imaging techniques such as abdominal x ray and chest x ray are useful to detect any past episodes of tuberculosis ( upper zone fibrosis and adrenal calcification are detected on the x ray and CT scan. ) The adrenal CT scan is useful to detect tuberculosis; histoplasmosis and metastases cancer. MRI scans of the head are useful to visualize any hypothalamus / pituitary lesions. (Secondary adrenal insufficiency).

Other tests may include investigation for tuberculosis, pernicious anemia, hypoparathyroidism , gonadal dysfunction and investigation of fasting blood glucose level in children.

How to manage adrenal insufficiency?

In acute setting (Addisonian crisis)

Fluid replacement therapy is required. IV fluid (0.9% saline solution for 1L) is given for the first 30 - 60 minutes. This is followed with 2L of 0.9% saline solution for 12 - 24 hrs. At the same time, the baseline blood test is performed that includes measurement of the cortisol level. It is requested immediately. Glucose is given if the patient is hypoglycemic. ( 50ml of 50% of dextrose solution).

Then, consider hydrocortisone therapy. 200 mg bolus of hydrocortisone is given intravenously. This is followed later with 100 mg of hydrocortisone which is administrated intravenously for every 6 hour or 10 mg/hr and continue the infusion until the patient is stable enough to consider an oral intake of hydrocortisone. Finally 40 mg of hydrocortisone is given in a divided dose daily. (10mg, 10mg, 20 mg).

Treat any precipitating infection with antibiotics.

Monitor the temperature, pulse, blood pressure, respiratory rates and oxygen saturation and urine output.

Medical treatment includes long term glucocorticoid replacement with hydrocortisone tds ( three time daily in divided dose such as 10 mg, 5mg, and 5mg ) or bd( twice daily in divided dose such as 20 mg in the morning and 10 mg in the evening ).The purpose of the divided dose is to mimic the physiological diurnal variation of cortisol secretion. Dexamethasone and Prednisolone are also useful due to its longer half life.

Treatment with steroid may require further monitoring in term of blood pressure and the fluid status as well as the clinical features of excess glucocorticoid)

Fludrocortisone is useful as a replacement for aldosterone/ mineralocorticoid deficiency. Urea and electrolytes are required to monitor the initial progress of the treatment. (Sodium, potassium and renin level are measured to make sure all of them are at the normal levels).

Individual glucocorticoid replacement therapy is based on daily cortisol level.

Patient education on glucocorticoid therapy may include:

-Do not stop, reduce or missed any doses of steroid.

-Remember to wear steroid medical alert bracelet and steroid card.

-Double the dose of steroids in case of febrile illness, stress and injury.

-Seek medical advice on how to perform an intramuscular injection of hydrocortisone in severe illness and the patient is unable to take the drug orally or suffer from severe and prolonged vomiting.

What is the prognosis adrenal insufficiency?

Delay in treatment may lead to mortality and morbidity. Untreated cases may lead to fatality and increase the risk of developing other autoimmune disorder both endocrine and non endocrine. The prognosis of adrenal insufficiency causes by other disorders depends on the prognosis of the underlying disorder. The most common cause of death from Addison disease/ adrenal insufficiency are due to infection and Addisonian crisis. Mean age of death in men is around 65 years old.

Hyperpigmentation of the gum
Hyperpigmentation of the gum
Hyperpigmentation of the right hand
Hyperpigmentation of the right hand
Hyperpigmentation of the buccal mucosa
Hyperpigmentation of the buccal mucosa

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